DESCRIPTION The analgesic properties of cannabinoids have been known for centuries. Additional therapeutic avenues for cannabinoids include appetite stimulation, lowering of intraocular pressure, relief from emetogenic effects of cancer chemotherapy, and immunomodulation. Despite these potential applications, cannabinoids are associated with therapeutically undesirable psychotropic side effects. Identification of both central (CB1) and peripheral (CB2) cannabinoid receptor subtypes provides a template for the design of non-centrally acting agents devoid of psychotropic effects. To separate the desirable from undesirable effects involves molecular characterization of CB1 binding sites, which can then be compared and contrasted to CB2. To this end, covalent affinity labels for CB1 and CB2 have been developed, which allows investigation of non-dissociable CDB1: ligand interactions to characterize at the molecular level, the respective ligand binding sites of these two receptors. Specific aims for this project are to: (1) identify covalent probes for CB1 and CB2 with respect to their ability to irreversibly occupy these receptors; and (2) identify and map ligand binding domains via immunoprecipitated enzymatic digests of radioiodinated affinity labeled CB1 and CB2.